This award provides salary support for investigations dealing with the mechanisms of B-lymphocyte differentiation. The goals of my research are to obtain information on the genetic regulation of a differentiation process which begins with an uncommitted stem cell and ends with a mature antibody-secreting plasma cell. The major methods used in dissecting the steps in this process involve analysis of the class of immunoglobulin expressed on the surface of the B lymphocyte, and the relationship of this class to the class of immunoglobulin secreted by fully differentiated progeny. Previous work in this area has shown that synthesis of micron chains precedes expression of any other class during development, thus indicating a developmental switch in CH gene expression. This switch was most clearly demonstrated by experiments in which mice and chickens were made deficient in all elements of the B cell line by treatment with anti-mu antibodies. The animal model thus provided is currently being used to examine the role of B cells and their products in development of tolerance, and in protection from transplanted or virally induced malignancies. Other investigations are concerned with the mechanisms of B cell triggering and of anti-micron suppression in vitro. We have developed a culture system in which murine lymphocytes can be induced to become plasma cells synthesizing IgM, IgG, and IgA by bacterial lipopolysaccharide, and have shown that anti-micron antibodies can block this process. We are investigating the ontogeny of this response and the differences among diverse lymphoid populations both as regards triggering and susceptibility to suppression. These experiments should generate information on different sub-populations of B lymphocytes. We have recently found major exceptions to the rule that a single plasma cell secretes a single species of antibody molecule. The stimuli which induce simultaneous synthesis of more than one immunoglobulin class by single cells are being explored. Finally, we are studying the blocks of lymphoid differentiation which lead to immune deficiency or are associated with lymphoid malignancy. The major tool utilized is analysis of the capacity of cultured B lymphocytes to be triggered to terminal differentiation by pokeweed mitogen. This process requires T cells, and therefore provides a useful way of analyzing both T and B cell abnormalities.